With funding from a pilot project from the Harvard Center for Medical Countermeasures against Radiation, we have utilized sophisticated mouse genetics to determine the role of the intrinsic pathway of apoptosis in the acute radiation syndrome. Through these studies, we have dissected the cellular target of radiation in the GI syndrome and these data suggest that mitotic death (rather than apoptotic death) of GI crypt epithelial cells causes crypt destruction that leads to the GI Syndrome. In this application, we will test this model using a combination of mouse genetics and small molecule inhibitors to block mitotic death. These studies will help define the mechanism of action of a novel medical countermeasure, which we have shown protects mice from the GI Syndrome. The overall goal of this application is to understand the mechanism of action of this countermeasure and to define the pharmacokinetics and pharmacodynamics of this product, so that it can be developed into a safe and effective agent to help minimize damage and restore GI function after radiation exposure.